The long-term goal for this project is to elucidate the specific molecular and cellular mechanisms that underlie chronic pain. Understanding these mechanisms will guide the development of new drugs and treatment strategies to better treat this pervasive public health burden. This proposal tests the hypothesis that closely related extracellular-signal regulated kinase (ERK) isoforms, ERK1 and ERK2, play distinct functional roles in chronic pain. Pharmacological experiments indicate that ERK1 and/or ERK2 are necessary for behaviors observed in well-characterized rodent models of pathological pain. To test if ERK1 is necessary for behavioral sensitization in these models, I will compare the behavioral responses of conventional ERK1 knockout mice with wildtype littermates. Unfortunately, conventional ERK2 knockout mice die during development, preventing their use in behavioral experiments. Nevertheless, the behavioral analysis of mice lacking ERK1 will provide valuable information about the function of ERK2, since we know from pharmacological studies that ERK1 and/or ERK2 is involved. Studies using the same pharmacological tools indicate that ERK1/2 is necessary for the sensitization of spinal cord dorsal horn neurons, which is likely to contribute to behavioral sensitization in pain models. To test the necessity of each individual isoform in these cellular changes, I will eliminate either isoform in spinal cord dorsal horn primary cultures. I will then determine whether cellular plasticity changes associated with sensitization occur in these neurons. Sensitization also occurs elsewhere in the pain neuraxis. Nociceptors, which transduce peripheral noxious stimuli, are sensitized in pain models, and ERK1 and/or ERK2 have been implicated in this process. Preliminary results indicate that ERK1 knockout mice show responses similar to those of wildtype littermates in inflammatory pain models, which partially depend on nociceptor sensitization. To test the hypothesis that ERK2 is necessary for nociceptor sensitization, I will create a conditional nociceptor-specific ERK2 knockout and test the behavioral responses of this mouse in models of inflammatory pain. These experiments will be the first to address the isoform-specific roles of ERK1 and ERK2 in pain. Results from this proposal will provide insight into the cellular and molecular mechanisms of chronic pain.